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COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP) RAPID ALERT

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COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP) RAPID ALERT Powered By Docstoc
					                           The European Agency for the Evaluation of Medicinal Products
                           Human Medicines Evaluation Unit

                                                                   London, 20 June 1996
                                                                  CPMP/PhVWP/005/96




   COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS
                      (CPMP)




    RAPID ALERT SYSTEM (RAS) IN PHARMACOVIGILANCE




DISCUSSION IN THE PHARMACOVIGILANCE WORKING PARTY                             May 1996

APPROVAL BY THE CPMP                                                          June 1996




                  7 Westferry Circus, Canary Wharf, London E14 4HB, UK
                 Switchboard: (+44-171) 418 84 00 Fax: (+44-171) 418 85 51
               E_Mail: mail@emea.eudra.org http://www.eudra.org/emea.html
                     NOTE FOR GUIDANCE ON
        RAPID ALERT SYSTEM (RAS) IN PHARMACOVIGILANCE

INTRODUCTION:

During the marketing period of a medicinal product urgent measures to safeguard public health
may be necessary. Within the European system of pharmacovigilance it is essential that
information concerning safety hazards possibly resulting in major changes to the marketing
authorisation status or withdrawal of a product, is exchanged between the Member States, the
Commission and the Agency in the case of centrally authorised medicinal products with the
appropriate degree of urgency.

An early exchange of information will enable the competent authorities to initiate data research
and seek specialist expertise so that necessary decisions may be taken as soon as possible.
Therefore the competent authorities of the Member States run the Rapid Alert System (RAS) in
accordance with the procedure laid down in this guideline.


PURPOSE:

The RAS alerts other Member States, the Commission and, in the case of centrally authorised
medicinal products, the Agency with the appropriate degree of urgency, to pharmacovigilance
data for medicinal products which indicate that action could be needed urgently to protect public
health. It is essential that communication of such problems occurs at an early stage, normally
before a decision is taken in a Member State.

The issue may be discussed then in a broad manner

•   in the Working Party on Pharmacovigilance on the basis of an assessment report,
•   in the CPMP
•   or formalised within procedures laid down in Article 12 and 13 of Directive 75/319 as
    amended or Article 18 of Regulation 2309/93.


SCOPE:

The RAS should be used in problems relating primarily to safety of medicinal products licensed
according to Directive 65/65 EEC and Regulation 2309/93. The system must not be saturated by
the transmission of less urgent information. The Infofax-system should be used to transmit less
urgent problems.

Rapid alerts regarding quality problems or concerning special batches of a medicinal product are
not considered in this guideline. Those Rapid Alerts must be handled as laid down in the
document III/5698/94-EN "Compilation of Community procedures on administrative
collaboration and harmonisation of inspection", worked out by the Working Party on control of
Medicines and Inspections in 1994 or further updates.


CRITERIA:

The RAS should be used when a Member State has concern about a change in the balance between
risks and benefits of a medicinal product and therefore major changes in the status of approval
seem to be necessary. A need to inform professionals or users about the identified risk without
delay may be an additional reason for sending a rapid alert. Normally the case relating to the
suspicion or concern is formulated by one Member State after evaluation of the data available in
that Member State and any other relevant information available.


CPMP/PhVWP/005/96                               1
With regard to a certain medicinal product or active ingredient authorised according to the
Directive 75/319 as amended or Regulation 2309/93 suspicion or concern may be based on:

•    report(s) of unexpected and serious ADRs

•    reports of an expected ADR which suggest greater severity or long-term sequelae than known
     or which identify new risk factors

•    increase in the reporting rate of expected serious ADRs

•    evidence from formal studies (clinical trials or epidemiological studies) indicative of
     unexpected risk or a change in frequency or severity of a known risk

•    knowledge that the efficacy of a medicinal product is not established as assumed to date

•    evidence that the risks of a particular product are greater than alternatives with similar
     efficacy.


Major changes in the authorisation status may be:

•    recall of the drug from the market
•    suspension or withdrawal of the marketing authorisation
•    changes in the SmPC, i.e. new contraindications, restriction of indications, reduction in dose
     or restriction in the availability of a medicinal product.


PROCEDURE:

I.      SENDING A RAPID ALERT:

Presently the most efficient means to transmit this kind of information and available in all
Member States is Telefax. Electronic transmission of information is being piloted between some
Member States and will be the future mode of information exchange. The establishment of pre-
defined data formats is essential to ensure collection of similar data, aid in exchange of
information among the Member States, and assist common evaluation. Proposed forms are
enclosed with this guideline.

If using the RAS the Member State should comply with the following rules:

a) The fax should be headed clearly as a RAPID ALERT at the top.

b) The fax should provide clear and concise information on the reasons for the Rapid Alert so
   that there is no need for clarification in the first instance.

c) The Member State generating the alert should transmit at least the minimal data listed in
   Annex I and form A.

d) Any information required from recipients should be specified clearly.

e) The fax should be preferably typewritten; the size of the letters should be large enough to
   ensure that the text is satisfactory readable.

f) Annexes to the fax form should be used if necessary to give sufficient details.

g) The fax should be transmitted to the contact points of the Member States, the Agency and to
   the Commission.



CPMP/PhVWP/005/96                                2
h) In case of urgency, when the Member State concerned has suspended the marketing
   authorisation of a medicinal product or withdrawn the drug from the market in order to
   protect human or animal health or the environment, the Agency and all Member States will
   be informed at the latest on the following working day.

i)    The Member State generating a Rapid Alert should inform the MA holders concerned in his
      country adequately and promptly. Receiving Member States are responsible for informing MA
      holders in their own countries. Information of the MA holders may be given via associations
      of the MA holders both in sending or receiving Member States.


II.      FOLLOW UP PROCEDURE

Responses from Member States

Responses to a specific Rapid Alert should be sent only to the originating Member State and the
Agency not later than one week of receipt of the fax. The heading of these forms (see form B)
should be "ANSWER TO RAPID ALERT". The information requested by the generating
Member State should be provided.

Assessment Report

The originating Member State should collate all information received from the Member States
and prepare an interim assessment report within five weeks after transmission of the initial Rapid
Alert to all Member States and the Agency. When the collated information provides evidence of
a serious safety concern the originating Member State should prepare a full risk-benefit
assessment report for consideration by the Pharmacovigilance Working Party. This should
follow the form and content of the guideline on Assessment Reports (Annex II) and following the
template (Annex III). This should be sent to all Member States, the Agency, and the
Commission, and should be considered at the next meeting of the Pharmacovigilance Working
Party. Consideration will need to be given to whether the matter is of Community interest and
should be referred under Article 12 of Directive 75/319 as amended.

The Agency will collate the information and compile the basic data from the Rapid Alerts and
will include conclusions in the "Drug Monitor Form".




CPMP/PhVWP/005/96                                3
                                           Annex I

          Information for transmission of information about detected signals
                   Minimal data that should be filled in every case


1. Identification:

•   Type of message categories: Rapid Alert/Non-urgent Message
•   Reference
•   From:
•   To:
•   Date:

2. Drug(s)

•   Brandname(s):
•   Active substance(s): (INN, DCI)
•   Pharmaceutical form and dosage (if appropriate):
•   Marketing authorisation holder(s)
•   Manufacturer (if essential)

3. Reason for Alert

•   Source of information: Spontaneous reports/Post-Marketing Study/Clinical Trial/Pre-clinical
    Study
•   summarised evidence relevant to alert

4. Actions

•   Action(s) proposed
•   Action(s) taken (steps taken to collect more information at a national level and temporary
    steps taken to limit risks)

5. Information exchange

•   Information required




CPMP/PhVWP/005/96                              4
                                             Annex II

                             Pharmacovigilance Assessment Report

                                        Format and content


I.        Introduction

This section should clarify why the assessment has been undertaken.

II.       Assessment of risks

This section will be specifically devoted to the safety concern under evaluation. It should
encompass all relevant sources of information, including spontaneous reports, published
literature, studies (pre-marketing clinical trials, postmarketing studies, epidemiological studies and
intensive monitoring data), other data, e.g. mortality data to:

a)     characterise the problem (nature, severity, outcome);
b)     assess causal association;
c)     estimate frequency and comparative frequency, where possible;
d)     provide evidence of risk factors

III.      Assessment of benefits

It should take into account the following, where known:

a) the nature of the illnesses for which the medicine is indicated (e.g. fatal, life-threatening,
   disabling, self-limiting, etc.)

b) absolute efficacy, as judged by placebo-controlled clinical trials

c) relative efficacy, as judged by studies comparing efficacy with that of appropriate alternative
   treatment(s)

d) the characteristics of the population exposed to the medicine (e.g. elderly and hospitalised,
   young and healthy, etc.)

IV.       Overall risk-benefit evaluation

This section includes:

a) an overall benefit/risk analysis in the context of the safety problem under assessment and
   relevant comparative safety with other drugs in the same class or for the same therapeutic
   indication;

b) discussion of the options for improving the risk-benefit ratio

c) recommended options for responding to the safety issue.




CPMP/PhVWP/005/96                                 5
                Annex III




             TEMPLATE FOR



FINAL REPORT FOLLOWING THE RAPID ALERT

                   OF



         < ACTIVE INGREDIENT >



       Status: < for INFORMATION >
                                TABLE OF CONTENTS




PRODUCT PROFILE AND ABSTRACT OF THE PROCEDURE


BACKGROUND INFORMATION

        Starting Point
        Referral to national advisory board
               The proceedings of the national inquiries
        Alerting the Member States
        Involvement of the CPMP Pharmacovigilance Working Party

SCIENTIFIC DISCUSSION

        Overview of the safety concerns
        Overview of benefits
        Overall risk - benefit assessment

PROPOSED ACTIONS / ACTIONS TAKEN

        National variation of marketing authorisation
        National suspension of the marketing authorisation
               National withdrawal of the marketing authorisation
        Referral to CPMP
ANNEXES




Template : Final report of RA               31 May 1996             Page 2
ABSTRACT OF THE ALERT PROCEDURE AND PRODUCT PROFILE (on one page)


        Alerting Member State

        Problem/Subject

        Drug
                 •   INN name
                 •   Brand name(s)
                 •   Strength(s)
                 •   Pharmaceutical form(s)
                 •   Route of administration
                 •   Therapeutic Classification (ATC-code)

        Indications

        Reason for Alert

        Proposed action or action taken




Template : Final report of RA                  31 May 1996      Page 3
BACKGROUND INFORMATION ON THE PROCEDURE


        Starting Point
                 •   When
                 •   By whom
                 •   The concern
                 •   The drug
                 •   The source of the concern
                     (e.g. case reports from spontaneous reporting, epidemiological study)

        Referral to the National Advisory Board
                 •   When
                 •   Which matter
                 •   Followed national inquiries (e.g. Stufenplan)

        The proceedings of the National inquires
                 •   When
                 •   On which problem
                 •   On which substance
                 •   Involvement of the marketing authorisation holders
                     ⇒ Time frame
                     ⇒ Explanations of the MAH(s) in writing/orally

        Alerting the Member States

                     When, by (e.g. Fax, e-mail)
                     On which problem
                     On which INN-name
                     Call for (e.g.)
                       case reports
                       details of legal status in the Member State
                       information on supply and use
                     Answers received from

        Involvement of the Pharmacovigilance Working Party

                 •   The subject was
                     ⇒ presented by, when
                     ⇒ discussed on, when
                 •   Additional explanations of the MAH(s) were given
                     ⇒ when
                     ⇒ in writing (expert report)
                     ⇒ orally
                 •   Assessment reports were prepared
                     ⇒ by , when
                     ⇒ reviewed, updated, finalised
                 •   A report of the Pharmacovigilance Working party was given
                     ⇒ when
                     ⇒ to (e.g. the CPMP, the MAH, others)

Template : Final report of RA                 31 May 1996                                    Page 4
SCIENTIFIC DISCUSSION
                 •   Overview of the safety concerns
                     ⇒ Adverse drug reactions
                     ⇒ Risk of correct treatment (e.g. defined populations at risk)
                     ⇒ Risk of inappropriate treatment (if applicable)
                 •   Overview of benefit
                     ⇒ Efficacy of drug
                     ⇒ Effectiveness of drug treatment
                 •   Overall risk - benefit assessment
                     ⇒ of drug under consideration
                     ⇒ place on the market
                     ⇒ compared to alternative treatment(s)

PROPOSED ACTIONS / ACTIONS TAKEN

                 •   Variation of the marketing authorisation
                     ⇒ Proposed conditions of supply and use
                     ⇒ Proposed warnings of health professionals and/or patients (e.g. Dear
                       Doctor Letter)
                     ⇒ Proposed changes of the SPC or parts of it
                     ⇒ Provision of further evaluation for the MAH(s)

                 •   Suspension of the marketing authorisation
                     ⇒ from, to
                     ⇒ with obligation to fulfil in between
                 •   Withdrawal of the marketing authorisation
                     ⇒ in force from
                     ⇒ recall of products on the market is included
                 •   Referral to CPMP
                     ⇒ Community interest involved

ANNEXES

        (Annexes if appropriate, )




Template : Final report of RA                31 May 1996                                      Page 5
                                           Form A

                      Sign of the competent authority of the Member State


                                 RAPID ALERT IN
                               PHARMACOVIGILANCE
                                    URGENT
Reference                       No of pages                     Date

                                No of annexes
FROM/EXPEDITEUR

TO:     ALL MEMBER STATES
        THE COMMISSION
        EMEA
        CHAIR-CPMP




                                   SUBJECT / OBJET:

Brandname:

Substance (INN, DCI):

Formulation and dosage (if appropriate):

Manufacturer (if essential):



                REASONS FOR ALERT / RAISON DE L’ALERTE
Keywords
        REASONS OF ALERT / RAISON DE L’ALERTE:
                          (Text)




         PROPOSED ACTION AND ACTION TAKEN /
        MESURES ENVISAGEES ET MESURES PRISES:
                          (Text)




           INFORMATION REQUESTED /
    INFORMATION DEMANDEE AUX DESTINATAIRES:
                          (Text)




                 ADDITIONAL INFORMATION /
                INFORMATION ADDITIONELLE
                          (Text)




Signature / Signature:
                                           Form B


                      Sign of the competent authority of the Member State


                           ANSWER TO RAPID ALERT
                           IN PHARMACOVIGILANCE

Reference                       No of pages                     Date

                                No of annexes
FROM/EXPEDITEUR

TO:     [THE ORIGINATING MEMBER STATE]
        EMEA
        OTHER RECIPIENTS




                                     SUBJECT / OBJET:

Brandname-

Substance (INN, DCI):

Formulation and dosage (if appropriate):

Marketing authorisation holder(s):

Manufacturer (if essential):
                   ANSWER TO RAPID ALERT:
                            (Text)




         PROPOSED ACTION AND ACTION TAKEN /
        MESURES ENVISAGEES ET MESURES PRISES:
                            (Text)




                 ADDITIONAL INFORMATION /
                INFORMATION ADDITIONELLE
                            (Text)




Signature / Signature:

				
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